The generation of diversity is a hallmark of the malignant process. This diversity results in the observed heterogeneity in tumor cell properties, the acquisition of metastatic capacity and the development of resistance to treatment. Diversity could be the result of accumulated, random point mutations and cell selection. An alternative, which has recently gained in experimental support, is that tumor diversity is promoted through cell-cell fusion and chromosome selection. The goal of our study is to extend these findings and critically assess the contribution of cell fusion to tumor development and progression using sensitive, unambiguous and nonselective markers for fusion events. This will be accomplished by analysis of the formation of heteropolymers of autosomal, multimeric alloisozymes in tumor-bearing allophenic (tetraparental, chimeric) mice. The results obtained will be independent of host cell contamination, can be analyzed on a tissue or individual cell basis, and will be free of histocompatibility effects or selection. Appropriate marker enzymes are available representative of different chromosomes, including glucose phosphate isomerase, malate dehydrogenase, phosphoglucomutase, isocitrate dehydrogenase and autosomal glucose-6-phosphate dehydrogenase. The primary tumor system to be employed is the methylcholanthrene-induced sarcoma. Using this system, the aims of our study are to determine the contribution of cell fusion to tumor development, to metastatic progression and to the acquisition of resistance to therapy, and to identify the cell partner for tumor fusion events. The results of these studies could provide greater insight into the pathogenesis of malignancy and the mechanisms by which tumors respond to their environment.